Cyclin-dependent kinase (CDK) and cyclin are important factors in the regulation of cell cycle. CDK can form a heterodimer with cyclin, wherein CDK is a catalytic subunit, cyclin is a regulatory subunit, and various cyclin-CDK complexes are formed, phosphorylating different substrates, thereby promoting and transforming the different phases of a cell cycle.
There are at least 9 CDKs in mammals. The transition from G1 phase to S phase in cells is mainly controlled by G1 phase CDK kinase. CDK kinases that bind to G1 cyclins mainly comprise CDK2, CDK4, and CKD6. Cyclin D mainly binds to CDK4 and CKD6 and regulates the activity of the latter; cyclin E binds to CDK2 at G1/S phase, exhibiting CDK2 kinase activity and promoting cell's entry into S phase. G2/M phase is mainly regulated by CDK1 kinase, Cyclin A and Cyclin B bind to CDK1, and CDK1 phosphorylates the substrate protein, such as histone H1 phosphorylation can cause chromosome condensation, or lamin phosphorylation can cause disintegration of nuclear membrane. During M phase, M-promoting factor (MPF) activates an anaphase-promoting complex APC, which is ubiquitously linked to Cyclin A and Cyclin B. With polyubiquitylation, they are degraded by a proteasome, which completes a cell cycle (Malumbres M. et al. Nat Cell Biol 11:1275, 2009; Malumbres M. et al. Nat Rev Cancer 9:153, 2009).
In the past decade, CDK inhibitors have been regarded as a hot spot for developing new anti-tumor drug in the global pharmaceutical industry, and more than 20 CDK inhibitors have entered clinical development. Although CDK inhibitors have significant preclinical anti-tumor pharmacodynamics, the results of most previous clinical trials were unsatisfactory. The main problems include lack of efficacy on solid tumors and the toxicity (Guha M. Nat Rev Drug Dis 11:892, 2012). During the analysis of serious toxic side effects, it was found that some CDK inhibitor drugs lack selectivity for CDK subtypes, resulting in greater side effects.
CDK4 and CDK6 are two closely related kinases that bind to Cyclin D during the tumor cell cycle and cause transition of G1 phase to S phase, which is essential for the cell cycle progression of DNA replication for cell division. Changes in the G1-S phase transition control mechanism through various genetic and biochemical adaptations have been found in more than 90% of human tumors. P16 and human retinoblastoma (Rb) are important tumor suppressor proteins that regulate cell cycle. P16 gene protein inhibits the feedback loop of CDK4, Cyclin D1 and Rb, and prevents the cell from hyperproliferation by regulating the protein activity of Rb for tumor suppression. It has been shown that activation of CDK4 and CDK6 causes changes in cell cycle in human tumors (such as breast tumor and myeloma). Inhibition of CDK4 and CDK6 can prevent inactivation of tumor suppressor protein Rb and interfere with tumor cell cycle progression (Choi Y J and Anders L, Oncogene 33:1890-903, 2014).
CDK4/6 plays a key role in the dysregulation of cell cycle control in various solid tumors and hematological tumors. There are several selective CDK4/6 inhibitors in clinical stages at present (e.g., Palbociclib, LY2835219, and LEE011). The clinical evaluation of these drugs also includes metastatic breast cancer, ovarian cancer, liposarcoma, non-small cell lung cancer, liver cancer, glioblastoma, melanoma, multiple myeloma and lymphoma and the like.
Although many CDK inhibitor compounds have been disclosed, a variety of drugs, particularly CDK4/6 inhibitors for treating CDK-related disorders are still needed due to CDK-mediated pathology.